The Role of I1-Imidazoline and α2-Adrenergic Receptors in the Modulation of Glucose Metabolism in the Spontaneously Hypertensive Obese Rat Model of Metabolic Syndrome X

We examined glucose metabolism after I 1 -imidazoline (I 1 R) and α 2 -adrenergic receptor (α 2 AR) activation in an animal model of metabolic syndrome X. Fasted spontaneously hypertensive obese rats (SHROB) were given the I 1 R/α 2 AR agonists moxonidine and rilmenidine or the α 2 AR agonist guanabenz. Because of the dual specificity of moxonidine, its actions were split into adrenergic and nonadrenergic components by using selective antagonists: rauwolscine (α 2 AR) efaroxan (I 1 R/α 2 AR), or 2-endo-amino-3-exo-isopropylbicyclo[2.2.1.]heptane (AGN 192403) (I 1 R). Hyperglycemia induced by moxonidine, rilmenidine, and guanabenz resulted from inhibition of insulin secretion. Similar responses were observed after oral dosing and in lean littermates. Glucagon was reduced by the I 1 R agonists (moxonidine, 32 ± 5%; rilmenidine, 24 ± 7%) but elevated by guanabenz (71 ± 32%). The hyperglycemic and hypoinsulinemic responses to moxonidine were blocked by rauwolscine. In contrast, rauwolscine potentiated the reduction in glucagon (39 ± 6%). AGN 193402 blocked the glucagon response without affecting hyperglycemia and hypoinsulinemia. Efaroxan blocked all responses to moxonidine. When SHROB rats were treated with moxonidine 15 min before an oral glucose tolerance test, the glucose area under the curve (AUC) was increased. Antagonizing the α 2 AR component of moxonidine9s action with rauwolscine improved glucose AUC 3-fold and facilitated the insulin secretory response and reduced glucagon secretion. Testing fasting glucose and insulin during 3 weeks of oral moxonidine revealed early hyperglycemia that later faded, and a progressive drop in fasting insulin. The acute hyperglycemia and hypoinsulinemia elicited by moxonidine and rilmenidine was mediated by α 2 AR, whereas I 1 R may reduce glucagon and increase insulin, particularly after a glucose load.